The long term objective of this proposal is to develop a novel cell-based system for creating influenza-virus like particle (VLP) vaccines against epidemic and potentially pandemic influenza viruses. This strategy will generate in a rapid and safe manner VLP structures that morphologically and biochemically resemble wild type virus, but are devoid of influenza genetic material and therefore non-infectious. Quadruple baculovirus recombinants will be used to express in insect cells the influenza structural proteins (M1, M2, HA, IMA) necessary for the formation and release of influenza VLPs from the cell surface. Replacement of the genes encoding the HA and NA, or both in the quadruple construct by those of the current epidemic (H3N2/Fujian) influenza virus or the HA and NA of influenza viruses with pandemic potential (H5N1, H7N7, and H1N1/1918) will allow us to create vaccines against these dangerous viruses in a safe manner. Candidate vaccines will be harvested and purified from the culture supernatant of insect cells infected with any of the four quadruple recombinants. The immunogenicity (local and systemic level) and protective efficacy elicited by these vaccines will be evaluated in mice and ferrets. Preliminary studies with a two component VLP vaccine in mice administered via either the intranasal or intramuscular route have demonstrated complete protection against a lethal influenza virus challenge. These results indicate the promise of this vaccine technology, which uses cell as production substrate, produces non-infectious entities, and is versatile enough to quickly accommodate emerging flu viruses. This will be a significant technological improvement in influenza vaccine production, and will facilitate the creation of vaccines against diverse influenza viruses and thereby protect the public from serious natural or perhaps intentional outbreaks of human influenza. [unreadable] [unreadable]